П N013765/01-091008 INSTRUCTION on medical use of medicinal product Progestogel Registration number: Trade name: Progestogel International nonproprietary name: progesterone Pharmaceutical form: gel for cutaneous application COMPOSITION per 100 g Active ingredient: natural micronized progesterone - 1 g Excipients: octyldodecanol, carbomer 980, macrogol glyceryl hydroxystearate (polyoxyl hydrogenated castor oil), trolamine (triethanolamine), ethanol calculated with reference to absolute ethanol 96% (v/v), purified water. Appearance: a colorless, semitransparent, slightly opalescent gel with odor of alcohol without visible particles. PHARMACOTHERAPEUTIC GROUP: gestagen ATC code: G03DA04 PHARMACOLOGICAL PROPERTIES Pharmacodynamics. The action of progesterone, on the one hand, is based on blockade of estrogen receptors resulting in an improvement of absorption of fluid from tissues, a decrease of compression of the milk ducts; on the other hand - on blockade of prolactin receptors in the breast tissue that leads to a reduction of lactopoesis. Thus, the local application of the product, by creating a high concentration of progesterone in the area of application does not exert the systemic action and makes it possible to avoid adverse side effects. The mechanism of action of Progestogel is based on an increase of progesterone concentration in the breast tissues. The active ingredient of the product is progesterone. Progesterone decreases expression of estrogen receptors in the breast tissues and also lowers the local level of active estrogens by stimulating production of enzymes (17-beta-hydroxysteroid dehydrogenase and estrone sulfotransferase) which oxidize estradiol into less active estrone and then by binding the latter transform it into inactive estrone sulfate. Thus, progesterone limits the proliferative action of estrogens on the breast tissues. Also, progesterone possesses the greatest natriuretic effect due to suppression of tubular reabsorption and increase of cellular filtration, thereby preventing retention of fluid at secretory transformations of the glandular component of the breasts and as a consequence, the development of pain syndrome (mastalgia or mastodynia). Along with that, Approved 09.20.2008 by RUS HA P. 1 transdermal method of gestagen administration allows also to provide an impact on the condition of the glandular epithelium and vascular network that results in a decrease of capillary permeability and consequently a reduction of severity of edema of the breast tissues and disappearance of symptoms of mastalgia. Pharmacokinetics. At transdermal administration Progestogel reaches tissues of the breasts without being destroyed in the liver and does not exert the systemic effects on the body. A study of serum concentration of prolactin, estradiol and progesterone during treatment with Progestogel has showed that one hour after the product application, when its maximum absorption in tissues of the breasts is observed, the level of hormones virtually does not change. Progesterone absorption at cutaneous application is about 10% of the dose. Cutaneous applications on the area of the breasts permit, on the one hand, to decrease the used dose of the product, and on the other hand, to create a high concentration in the area of action (as much as 10 times of that in the systemic blood flow). The product undergoes secondary metabolization in the liver with formation of conjugates with glucuronic and sulphuric acid. Isoenzyme CYP2C19 is also involved in metabolism. Eliminated by kidneys - 50-60%, in the bile - more than 10%. The amount of metabolites eliminated by kidneys varies depending on the phase of corpus luteum. INDICATIONS Indications Mastodynia Difuse Fibrocystic Mastopathy CONTRAINDICATIONS Nodal forms of fibrocystic mastopathy Tumors (tumor-like formations) of the breasts of unclear etiology Individual intolerance of any of the components of the product Cancer of breast and genitals (as monotherapy) Pregnancy (trimesters II and III) WITH CAUTION Hepatic insufficiency; renal insufficiency; bronchial asthma; epilepsy; migraine; depression; hyperlipoproteinemia, extrauterine pregnancy; incipient abortion; predisposition to thromboses, acute forms of phlebitis or of thromboembolic diseases; bleeding from the vagina of unclear etiology; porphyria; arterial hypertension; diabetes mellitus. Approved 09.20.2008 by RUS HA P. 2 PREGNANCY AND BREAST FEEDING There is no sufficient experience of using Progestogel during pregnancy. The use of the product during pregnancy and in the period of lactation is possible only if the expected benefit for the mother overweighs the potential risk for the fetus and child. ADMINISTRATION AND DOSAGE 1 application (2.5 g of gel) containing 0.025 g of progesterone is applied on the skin of the breasts with an applicator-dispenser until complete absorption 1-2 times daily or in the 2nd phase (from the 16th through the 25th day) of the menstrual cycle. The course of treatment - for up to 3 cycles. The repeated course of treatment may be prescribed only after a consultation with the doctor. SIDE EFFECTS Extremely rarely: tenderness of the breasts, hot flushes, metrorrhagia, decreased libido. In increased sensitivity to the product components - erythema at the site of gel application, edema of the lips and neck, fever, headache, nausea. OVERDOSE Overdose is unlikely due to a low systemic absorption. INTERACTION WITH OTHER DRUG PRODUCTS The action of Progestogel can increase against the background of contraception with combined hormone drugs. SPECIAL WARNINGS AND PRECAUTIONS Progestogel may be prescribed in mastodynia related to the use of oral contraceptives, pubertal period, premenopause, premenstrual syndrome. The product should be applied on the skin of the breast with an applicatordispenser without rubbing in it and massaging the breasts. Avoid exposure to direct sun rays after application of the cream. EFFECT OF THE PRODUCT ON THE ABILITY TO DRIVE A VEHICLE AND WORK WITH MECHANISMS There were no studies to reveal a possible effect of the product on the ability to drive a vehicle or to work with mechanisms. HOW SUPPLIED Gel for cutaneous application 1%. Approved 09.20.2008 by RUS HA P. 3 80 g of the product in AN aluminum tube closed with a screw cap. One tube in a carton together with a dosing applicator and the instruction on use Shelf life 3 years Do not use after the expiry date printed on the pack. STORAGE At a temperature not exceeding 25C Keep out of the reach of children! DISPENSING FROM PHARMACIES Prescription medicine. Name and address of the manufacturer: Laboratoires BESINS INTERNATIONAL 13, rue Périer, 92120 Montrouge, France Besins Manufacturing Belgium 128, Groot Bijgaardenstraat, 1620 Drogenbos, Belgium Approved 09.20.2008 by RUS HA P. 4